Cancer causes a substantial portion of all human deaths. Many cancers, such as lung cancer, continue to be resistant to known chemotherapy regiments; thus, there is a need to identify improved treatment methods.
Emerging evidence indicates that impaired cellular metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. One predominant metabolic abnormality is that cancer cells take up glucose at higher rates than normal tissue and favor aerobic glycolysis. In addition to the dependency on glycolysis, cancer cells have another atypical metabolic characteristic, that of increased rates of glutamine metabolism. Although the requirement for mitochondrial ATP production is reduced in glycolytic tumor cells, the demand for tricarboxylic acid cycle (TCA) cycle-derived biosynthetic precursors and nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) is unchanged or even increased. In order to compensate for these changes and to maintain a functional TCA cycle, cancer cells often rely on elevated glutaminolysis.
Glutaminolysis is a mitochondrial pathway that involves the initial deamination of glutamine by glutaminase (GLS), yielding glutamate and ammonia. Glutamate is then converted to alpha-ketoglutarate (alpha-KG), a TCA cycle intermediate, to produce both ATP and anabolic carbons for the synthesis of amino acids, nucleotides, and lipids. The conversion of glutamate to alpha-KG is catalyzed by either glutamate dehydrogenase 1 (GDH1, also known as GLUD1, GLUD, GDH) or other transaminases, including glutamate pyruvate transaminase 2 (GPT2, also known as alanine aminotransferase), and glutamate oxaloacetate transaminase 2 (GOT2, also known as aspartate aminotransferase), which convert a-keto acids into their corresponding amino acids in mitochondria. Fluxes of these enzymes are commonly elevated in human cancers. Glutaminolysis also supports the production of molecules, such as glutathione and NADPH, which protect cells from oxidative stress. Mounting evidence suggests that many types of cancer cells have tumor-specific redox control alterations, with increased levels of reactive oxygen species (ROS) compared with normal cells. A moderate increase in ROS can promote cell proliferation and differentiation, whereas excessive amounts of ROS can cause oxidative damage to proteins, lipid, and DNA. Therefore, maintaining ROS homeostasis is crucial for cell growth and survival. Cells control ROS levels by balancing ROS generation with their elimination by ROS-scavenging systems such as glutathione peroxidase (GPx), gluthathione reductase (GSR), thioredoxin (Trx), superoxide dismutases (SODs), catalase (CAT), and peroxiredoxin (PRX).
Alpha-KG, a product of GDH1 and a key intermediate in glutamine metabolism, is known to stabilize redox homeostasis in cells. Although elevated glutaminolysis and altered redox status in cancer cells has been theoretically justified, the mechanism by which alpha-KG regulates redox and whether this regulation is crucial for tumorigenesis and tumor growth remain elusive.
Jin et al. report Glutamate Dehydrogenase 1 signals through antioxidant Glutathione Peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell 27, 257-270.
References cited herein are not an admission of prior art.